Cartilage in the adult mammalian body occurs in three principal forms: hyaline cartilage; white fibrocartilage; and yellow elastic cartilage. Hyaline cartilage is chiefly present as articular cartilage in the synovial diarthroidal joints of the hip and shoulder and between the long bones where it forms the stiff and smooth articulating surfaces. White fibrocartilage is present in the menisci of the knee and temporomandibular joint of the jaw and in the intervertebral discs. Yellow elastic cartilage gives support to the epiglottis, Eustachian tube and external ear.
Three pathological conditions involving cartilage damage are very common: osteoarthrosis of articular cartilage; injury to the fibrocartilage of the knee menisci and collapse, rupture or herniation of the intervertebral disc.
Osteoarthrosis is caused by the progressive damage and breakdown of articular cartilage most commonly in the hip and knee and is an important cause of pain and reduced mobility in old people. Injury to the fibrocartilage of the meniscus is a common sports injury and is also seen as a result of road traffic accidents.
The structure and function of articular cartilage has been reviewed by Hasler E M, Herzog W, Wu J Z, Muller W, Wyss U. 1999 in their article, “Articular cartilage biomechanics: Theoretical models, material properties, and biosynthetic response” published in Critical Reviews In Biomedical Engineering vol 27 part 6 pages 415-488. Articular cartilage is highly specialized to provide a relatively frictionless, highly lubricated, wear resistant surface between relatively rigid bones. It also functions to transmit and distribute the forces arising from loaded contact to the surrounding cartilage and underlying subchondral trabecular bone. Hyaline cartilage is not thought to act as a shock absorber limiting the forces to the bone from impacts. This is because its volume for dissipating energy is very small compared to that of bone and because it actually increases in stiffness with increasing strain rate making it an inappropriate material for use as a shock absorber. Articular cartilage is a non-vascular connective tissue largely composed of a fluid phase consisting principally of water and electrolytes interspersed in a solid phase containing type II collagen, proteo-glycan and other glycoproteins. The latter constituents surround and are secreted by highly specialized mesenchymal cells, the chondrocytes which account for some 10% of the volume of articular cartilage. Healthy articular cartilage is strong and stiff (modulus between 1 and 20 MPa). The arrangement of the collagen fibrils within articular is essential to its function. They are arranged in a complex arcade structure forming columns arranged normal to and anchored in the osteochondral junction. These columns run up through the deep layer of cartilage but the predominant fibre orientation gradually changes to form the arches of the arcade structure in the superficial cartilage.
In the superficial layer which abuts the joint space, the meshwork of collagen fibrils is much denser while the fibrils are almost entirely tangential to the cartilage surface. The orientation of collagen in articular cartilage is vital to its mechanical function.
No wholly satisfactory procedure exists for replacing damaged articular cartilage in osteoarthrosis and instead artificial prostheses are most commonly used to replace the entire hip and knee joints. While these increase mobility and reduce pain they suffer from progressive wear, mechanical failure, adverse tissue reactions and loosening at their interphase with the bone.
The menisci of the knee joint are C-shaped discs interposed between the femoral condyles and tibial plateau and have the function of compressive load spreading, shock absorption, stabilization and secretion of synovial fluid for lubrication. The structure, function and pathology of the menisci have been reviewed by S. M. Bahgia and M. Weinick, Y. Xing, and K. Gupta (2005) Meniscal Injury, E-medicine World Library, 27 Jul. 2005. The outer rim is vascular while the central part is avascular fibrocartilage. Type I collagen (non-articular cartilage fibrillar collagen) accounts for about 70% to 90% of the collagen of the menisci. Most of the collagen is arranged in rope-like circumferential fibres together with fewer radial tie fibers. As in articular cartilage, collagen orientation is extremely important for the mechanical function and fixation of this structure. Compression of the meniscus leads to tensile hoop loading of the circumferential fibres and radial loading of the radial fibres, resisting spreading and flexing of the menisici. Thus the ability of the meniscus to spread load and dissipate energy is dependent on the integrity of the collagen fibre lay. For this reason damage to these fibres increases the risk of secondary osteoarthrotic damage to the condylar cartilages as the normal load distribution and shock-absorbing functions are impaired. The meniscofemoral ligament firmly attaches the posterior horn of the lateral meniscus to the femoral condyle and the coronary ligament anchors the peripheral meniscal rim to the tibia.
Meniscal injuries are fairly common in adults and are most frequently sports-related. They are less common in children over 10 years old and rare in children under 10 with morphologically normal menisci (Iobst, C. A. and Stanitski, C. L., 2000, Acute knee injuries. Clin Sports Med. 2000 Oct.; 19 (4):621-35).
Surgical treatment of damaged menisci is often necessary. Although total or partial meniscectomy was popular some forty years ago, it is now well understood that this procedure leads to articular cartilage degeneration (King, D. Clin. Orthop. 1990, 252, 4-7; Fairbank, T. J. J. Bone Joint Surg. Br. 1948, 30, 664-670). The extent of the degeneration of the cartilage appears to depend on how much tissue has been removed. Therefore partial meniscectomy is the current procedure of choice. However, even with partial mensicectomy, secondary osteoarthrosis is still a long-term consequence. Better alternatives to partial meniscectomy are therefore being sought. Allograft transplantation is a fairly successful alternative. However there is no proof that replacement of the meniscus with an allograft can re-establish some of the important meniscal functions, and thereby prevent or reduce the development of osteoarthrosis secondary to meniscectomy (Messner, K. and Gao, J. 1998 The menisci of the knee joint. Anatomical and functional characteristics, and a rationale for clinical treatment. Journal of Anatomy, 193:161-178). The major problems are the lack of remodelling of the graft resulting in inferior structural, biochemical and mechanical properties and insufficient fixation to bone. Further disadvantages include the shortage of suitable donors, difficulties with preservation techniques, the possible transfer of diseases, difficulty in shaping the implant to fit the donor and possible immunological reactions to the implant (Stone, K. R. Clin. Sports Med. 1996, 15, 557-571).
Total knee replacement cannot be considered as treatment for uncomplicated meniscal injury. Dacron and Teflon meniscal prosthetic components may initiate severe synovial reactions (Cook, J. L., Tomlinson, J. L., Kreeger, J. M., and Cook, C. R. 1999. The American Journal of Sports Medicine 27:658-665 Induction of meniscal regeneration in dogs using a novel biomaterial) while loosening and mechanical failure are a problem (de Groot, J. H. 1995 Doctoral dissertation. University of Gronigen, Summary p 153).
Partial or total meniscal replacements made from collagen, Teflon fibre, carbon fibre, reinforced polyester, or polyurethane-coated Dacron showed high failure rates resulting from poor fixation, mechanical failure or severe inflammatory response.
Elastomers based on amphiphilic urethane block copolymers have been suggested for meniscal repair and tested in an animal model. (Heijkants, R. G. J. C. 2004 Polyurethane scaffolds as meniscus reconstruction materials, Ph.D. Thesis, University of Groningen, The Netherlands, MSC Ph.D.-thesis series 2004-09; ISSN: 1570-1530; ISBN: 90 367 2169 5, chapter 10 pp 167-184) These materials are likely to produce less toxic degradation products than Dacron or Teflon. However, the mechanical properties of the polyurethanes tested did not match native meniscus very well and this may help to explain why only poorly orientated collagen was found in the regenerating fibro-cartilage in the implanted devices in place of the well-orientated collagen in normal meniscus. A further potential problem was that the polyurethane materials produced a Stage I inflammatory response (giant cells and some macrophages).
Recently, tissue engineering strategies for meniscal repair have been suggested including the use of biocompatible grafts as a substrate for regeneration, and cellular supplementation to promote remodeling and healing. Little is known, however, about the contributions of these novel repair strategies to restoration of normal meniscal function. (Setton, L. A., Guilak, F, Hsu, E. W. Vail, T. P. (1999) Biomechanical Factors in Tissue Engineered Meniscal Repair. Clinical Orthopaedics & Related Research. (367S) supplement:S254-S272, October 1999).
U.S. Pat. No. 4,344,193 (Kenny/Dow Chemical) appears to have been the first patent document to disclose the idea of a meniscal prosthesis rather than a total joint replacement endoprostheses. The meniscal prosthesis suggested is of non-reinforced silicone rubber. This material has low biocompatibility and would be likely to trigger a severe synovial reaction.
U.S. Pat. No. 4,502,161 (Wall) discloses a meniscal prosthesis of silicone rubber, rubber or polytetrafluorethylene with a reinforcing mesh of stainless steel strands, nylon or a woven fabric embedded within it. The suggested materials have low biocompatibility and would be likely to trigger a severe synovial reaction.
WO 89/00413 (Stone/Regen Biologics Inc.) discloses a prosthetic meniscus made of a three-dimensional array of collagen type I fibres interconnected via crosslinks consisting of polymerised glycosaminoglycan molecules. In vivo, the matrix has an outer surface contour substantially the same as that of a natural meniscus. The matrix provides a partially resorbable scaffold adapted for the ingrowth of meniscal fibrochondrocytes. Whilst the constructs may have a defined shape and size, the mechanical properties—in particular the compressive modulus—do not approach that of cartilage.
U.S. Pat. No. 4,919,667 (Richmond/Stryker) discloses a meniscal prosthesis constructed from polyester bonded with polyurethane. The polyester is arranged as a felt in one or more intermediate layers sandwiched between a woven cloth top and bottom layer also of polyester. The polyester and polyurethane are likely to be more biocompatible than the materials of U.S. Pat. No. 4,502,161.
U.S. Pat. No. 6,306,169 (Lee) discloses an implant consisting of a porous macrostructure the pores of which are filled up with a hydrated gel. The macrostructure is made of a bioresorbable polymer (collagen, gelatin, poly-L-lactic acid, polycaprolactone, polyhydroxybutarate, or polyanhydrides) and the non-porous, hydrated gel consists of alginate, agarose, carrageenans, glycosaminoglycans, proteoglycans, polyethyelene oxide or collagen monomers. This structure improves on the mechanical properties of the constructs of WO 89/00413, but still struggles to reach those of cartilage.
U.S. Pat. Nos. 6,514,515 and 6,867,247 (Williams) discloses the use of a bioresorbable and biocompatible polymer of polyhydroxyalkanoate for tissue repair. Such polymers may be tuned to have specific mechanical properties.
U.S. Pat. No. 6,679,914 (Gabbay) discloses a meniscal prosthesis comprising a plurality of superimposed sheets of animal pericardium cross-linked by an aldehyde.
WO 00/72782 (Wolowacz/Smith & Nephew) discloses a biocompatible, resorbable implantable material for total replacement or reinforcement of connective tissue consisting of a flexible tape containing aligned fibres. The application mentions the use of a hydrogel as a ‘carrier medium’ by means of which cells are incorporated into the material.
The structure and function of the intervertebral disc has been reviewed by Matcher, S J, Winlove, C P and Gangnus, S V., (2004) in their article, “The collagen structure of bovine intervertebral disc studied using polarization-sensitive optical coherence tomography” published in Physics in Medicine and Biology, volume 49 pages 1295-1306. A disc comprises an inner region, the nucleus pulposus surrounded by the annulus fibrosus. The inner nucleus pulposus is a visco-elastic gel constructed from proteoglycans trapped in a disordered network of fine type-II collagen fibrils. In contrast, the outer annulus fibrosus consists of axially concentric lamellae, constructed from larger fibrils of type I collagen and a considerably lower concentration of proteoglycans. The fibres run parallel to each other within each lamella of the annulus fibrosus but at a constant angle to the axis of the disc. This angle alternates from lamella to lamella to give a trellis-like structure in which the fibre angle increases as the disc is axially compressed. Thus the intervertebral disc has a somewhat similar structure and function to the meniscus, acting as a fluid-filled pressure vessel, whose function is to convert axial compressive forces into tensile forces in the collagen of the concentric lamellae of the annulus fibrosus. The collagen fibres of the annulus fibrosus at top and bottom of the disc are firmly anchored to the epiphyseal bone of the centra of the adjacent vertebrae.
WO 2005/094911 (Knight/Oxford BioMaterials Ltd.) discloses a composite material comprising one or more silk elements in an acrylic or cross-linked protein matrix and its use in a wide range of implantable devices. The application teaches the use of certain Wild silks naturally decorated with the integrin-binding tripeptide RGD. This tripeptide in Wild silks facilitates the binding of mesenchymal and other cells.
Thus, there is still considerable scope for improvement in the implantable materials and devices used for the repair or replacement of articular cartilage, intervertebral discs and menisci.
It is an object of the present invention to provide an implantable cartilaginous tissue repair device with mechanical properties which are closer to the anatomical requirements of the tissue to be repaired than those of prior art devices.
It is a further object of the present invention to provide a substantially bioresorbable implantable cartilaginous tissue repair device which allows and encourages the gradual infiltration and replacement of at least some parts of the device with autologous collagen and proteoglycans (i.e. collagen and proteoglycans produced by the patient's own body) more effectively than prior art devices.
In another aspect, it is an object of the present invention to provide an implantable tissue repair device which is at least partially bioresorbable and which has an effective means for being attached or anchored to a bone of a patient.